Trends of kidney cancer burden from 1990 to 2019 in European Union 15 + countries and World Health Organization regions

In recent decades, variability in the incidence and mortality of kidney cancer (KC) has been reported. This study aimed to compare trends in incidence, mortality, and disability-adjusted life years (DALY) of KC between the European Union (EU) 15 + countries and 6 World Health Organization (WHO) regions. The data of KC Age-standardized incidence rates (ASIRs), age-standardized mortality rates (ASMRs), and age-standardized DALYs were extracted from the Global Burden of Disease database. Joinpoint regression was employed to examine trends. From 1990 to 2019, the ASIR increased in most countries except for Luxembourg (males), the USA (females) and Austria and Sweden (both sexes). ASIR increased across all 6 WHO regions for both sexes except for females in Americas. The ASMR increased in 10/19 countries for males and 9/19 for females as well across most WHO regions. The mortality-to-incidence ratio (MIR) decreased in all countries and WHO regions. Trends in DALYs were variable across countries and WHO regions. While the incidence and mortality from KC rose in most EU15 + countries and WHO regions from 1990 to 2019, the universal drop in MIR suggests an overall improvement in KC outcomes. This is likely multifactorial, including earlier detection of KC and improved treatments.

Trends in KC ASIR, 1990-2019. Across the study period, there was a rise in ASIR globally for both males (+ 38.4%) and females (+ 13.5%). There was a similar trend across all six regions, with the Western Pacific region seeing the greatest increase in males (+ 142.8%), while the Eastern Mediterranean region saw the greatest increase in females (+ 98.4%). The Americas had the smallest increase in ASIR for males (+ 16.4%) and was the only region to observe a fall in ASIR for females (− 6.9%).
Amongst EU 15 + countries, Denmark had the greatest increase in ASIR for both males and females, + 89.3 and 82.8%, respectively. Austria was among the only three countries witnessing a fall in ASIR for males and saw the greatest fall (− 18.0%). Sweden saw the greatest fall in ASIR for females (− 24.0%).
Tables 1 and 2 and, Figs. 1, 2 depict gender-specific trends in KC ASIR across EU 15 + countries and 6 WHO regions. Table 1. 1990 and 2019 female age-standardized mortality rates (ASMRs), age-standardized incidence rates (ASIRs), mortality-to-incidence ratios (MIR), and disability-adjusted life years (DALYs), with associated percentage changes, for KC in the European Union 15 + countries and WHO regions. All indices are per 100,000 population.   Age-standardized incidence rates (ASIR) for females (a) and males (b), age-standardized mortality rates for females (ASMR) (c) and males (d), mortality-to-incidence ratios (MIR) for females (e) and males (f), and disability-adjusted life years (DALYs) for females (g) and males (h) for kidney cancer (KC) for EU 15 + countries in 2019. All indices are per 100,000 population. The Joinpoint analyses for ASMR in males and females are shown in Table 4              Trends in KC MIR, 1990-2019. Across the study period, there was a decrease in MIR globally for both males (− 13.7%) and females (− 13.9%). All EU 15 + countries saw a decrease in MIR across the study period. Portugal saw the greatest decrease in males with a − 29.0% fall, while Ireland saw the greatest decrease in females with a − 26.6% fall. Sweden saw the smallest decrease in males and females with only a − 11.7% and − 8.5% fall, respectively. These trends were reflected across WHO regions, where all regions saw decreases in MIR across the study period. The Western Pacific region saw the greatest decrease in MIR in males with a − 27.3% reduction, while the Western Pacific and Eastern Mediterranean region were equivalent for females with − 27.9% reductions. The Americas saw the smallest decrease in MIR for both males and females over the study period, − 6.9% and − 10.2%, respectively.

Discussion
In this study, we aimed to analyze the trends of incidence, mortality, mortality to incidence ratio, and DALYs associated with KC among EU15 + countries and 6 WHO regions, using the GBD study data and Joinpoint regression analysis. During a 29-year interval, while incidence and mortality from KC increased in most of the included countries, a drop in MIR was noted in all countries. Trends in DALYs were variable between countries. High-income countries had the highest values of ASIR, ASMR, and DALYs, concurring with previous studies 11, 23 . This could be partly attributed to a better performing cancer registry system and a higher prevalence of KCrelated risk factors 23 .
We found that the incidence of KC has been increasing in most EU15 + countries, which is congruent with previous reports 11,23 . The rise in incidence is likely in part due to greater detection of early-stage KC on crosssectional imaging and partly due to the increasing prevalence of smoking, obesity, and hypertension which are among the strongest risk factors of KC [5][6][7]11,24 . In terms of smoking, an addition of more than 200 million daily smokers was noted between 1980 and 2012, probably contributing to the development of KC worldwide 25,26 . However, recent declines in smoking rates have occurred in developed countries due to anti-smoking campaigns. This trend may be reflected by the decline in EAPC seen in the last decade in the high-income and upper-middle-income countries as per World Bank classification 23 . Similarly, worldwide obesity prevalence had doubled during the past decades, with increasing trends seen especially in developed countries 27,28 . This increase in obesity prevalence parallels our results showing that developed countries had a notable increase in incidence with the highest elevations noted in the World Bank upper-middle-income category for males. Occupational exposures to toxic compounds such as cadmium have also been found to elevate the risk of KC among males, however, to a lesser extent 29 . Even though the contribution ratio of occupational exposure to trichloroethylene to kidney cancer incidence and mortality was relatively weak in the GBD database, protection is mandatory in the organic/chlorinated solvent industry 23 . Recent analysis of risk factor contribution to global cancer burden in 2019 showed that for both sex combined, 33.8% of deaths could be attributed to risk factors analyzed with 19% attributed to High body-mass index, with 33% absolute increase since 2010, 18.1% attributed to smoking, with 19.1% absolute increase since 2010, < 1% attributed to occupational exposure to trichloroethylene, with 40.5% absolute increase since 2010 30 .
Another potential cause of the rising incidence is the higher utilization of imaging and discovery of incidental small renal masses, which account for nearly half of the new cases of renal cell carcinoma 31 . Detection of lower stage disease is associated with a better prognosis, and therefore the earlier detection of KC, as per the stage migration phenomenon, may be responsible for some of the improvements in patient outcomes 32 . Asymptomatic masses are more frequently diagnosed given the increased clinical use of modern imaging such as abdominal CT scans for evaluating urological and non-urological symptoms 11,33 . Indeed, a study in Canada showed an annual increase of CT imaging rates by 11.6% between 2000 and 2006, which decreased to 3.7% from 2013 to 2016 34  Similarly, CT use continuously increased for assessing abdominal pain in the emergency departments of the United States from 1997 to 2016, concurring with an increased ASIR for males in the USA 35 . The increased frequency of radiological diagnosis would not be the sole reason behind the rise in ASIR in low-income countries since it has been demonstrated that these countries do not have equal access to imaging modalities compared to high-income countries 36 . An improvement in healthcare access is noted in the Middle East and North Africa (MENA) region in the past few decades with a rise in life expectancy at birth from 65 years in 1990 to 71 years in 2012, which could reflect on the increased diagnosis of KC 37 . However, significant disparities among and within countries still exist, especially with the unregulated intervention of the private sector to fill the gaps of the governments' insufficient coverage, raising concern for equity 37 . Thus, a multifactorial model would be the ultimate explanation for the increased KC incidence in different countries.
Lower MIRs worldwide may be partly due to the stage migration with the detection of lower stage disease on cross-sectional imaging. These tumors are associated with a lower likelihood of cancer mortality, and 30% were indolent on post-operative pathology 38,39 . However, a recent article highlighted a paucity of imaging modalities www.nature.com/scientificreports/ in low to middle-income countries. Thus, over-diagnosis is not the only explanation for the universal drop in MIR 36 . We showed that mortality is also decreasing in most of the included countries. One plausible explanation for the mortality drop would be the approval of 10 novel drugs by the US Food and Drug Administration (FDA) for the treatment of metastatic RCC between 2005 and 2016, with the first approved targeted therapy being Sorafenib, a tyrosine kinase inhibitor (TKI) 40,41 . The inclusion of targeted therapies in the therapeutic arsenal of KC was proven by several studies to positively impact patients' survival [42][43][44] . Our results mirror these findings as we noticed a drop in EAPCs of ASMRs from 2005 onwards, during the era of targeted therapies, in the high-income and upper-middle-income classes in the World Bank classification. On the other hand, EAPCs of ASMRs were still increasing after 2005 in middle-low to low-income countries, possibly due to a lack of access to comprehensive multidisciplinary team care, clinical trials, and advanced treatment modalities such as stereotactic  www.nature.com/scientificreports/ radiotherapy medicine 45 . Additionally, now a subset of patients with metastatic RCC can be cured with immuneoncology (IO-IO) combinations but these recently entered into practice in 2018 46 . Therefore, future analysis will give information about its effects on survival and mortality. Poor access to treatment and imaging modalities plays a role in increased mortality rates in such regions since tumors are diagnosed at a later stage and are treated in a suboptimal manner 45 . Indeed, we highlighted that middle and low-income countries had higher increases in ASMRs and smaller drops in MIR than high-income countries. Similarly, a previous article had comparable conclusions to ours, having found a positive correlation between the availability of imaging examinations/ www.nature.com/scientificreports/ effective systemic therapies in high-income countries and a favorable prognosis; the authors also concluded that MIRs were negatively correlated with the human development index and the current health expenditure per capita 47 . In this setting, Fay et al. emphasized the importance of clinical trial enrollment as a solution to health disparities by concluding to a similar overall survival among patients with metastatic RCC recruited in clinical trials across different geographic regions, despite different baseline characteristics 48 . We observed that the DALYs were decreasing in most of included Western European countries, especially in females. However, the DALYs remained stable in the European region. This is probably attributed to an increase in DALYs in Eastern Europe as opposed to a decrease in Western Europe 49 . Finally, as we demonstrated an increase in incidence and mortality from KC in most included countries and regions, future focus is needed to implement strategies for the detection of early-stage KC. Extra efforts need to be put into decreasing the prevalence of smoking, obesity, and hypertension, which are among the strongest risk factors of KC, through campaigns and medical attention 50,51 . Although MIRs are decreasing, thus indicating an improvement in outcomes, equal access to treatment would ameliorate even more the situation worldwide, especially by using novel targeted and IO therapies 51 .

Limitations
Limitations following the use of the GBD database were noted previously by our group and the GBD Study collaborators 15,16,52 . Regarding this study, the first limitation is the presence of alterations in data coding systems and country-specific practice during the study period, markedly a shift from the use of ICD 9 to ICD 10. However, the GBD authors map mortalities to causes of death lists, adjusting by such to the different coding systems. Secondly, variability in the reliability of death certification exists both within and across countries, with worldwide errors in death certification ranging from 39 to 61% [53][54][55] . Also, only 39% of deaths globally were registered in 2012. Considering that Europe, the Americas, and Australasia were ranked among the best continents with civil registration and vital statistics 56 , we demonstrated valid data of the EU15 + countries and 6 WHO regions assessed. To balance the under-registration, the GBD uses garbage-code distribution algorithms and corrections 17,18 , which relate to deaths resulting from poorly defined diagnoses or those that cannot be the single underlying cause of death. Thirdly, we could not extract the subcategorized data by individual KC histological subtypes from the GBD Study results tool, which should be considered when interpreting the results. Indeed, histopathological subtypes and stages of KC amend to different clinical significance and urgent management. Finally, since our study is an observational analysis of the trends in the burden of KC across 29 years in EU15 + countries and 6 WHO regions, causal inferences cannot be concluded. Moreover, as seen in observational analyses, some potential confounders were not accounted for by using sex-specific, age-standardized incidence and mortality rates.

Conclusions
While the incidence and mortality from KC rose in most EU15 + countries and WHO regions from 1990 to 2019, the universal drop in MIR suggests an overall improvement in KC outcomes. This is likely multifactorial, including earlier detection of KC and improved treatments. These results are also of interest from a public health perspective as they highlight the importance of adjustable risk factor modification. A further study among lower-income countries would help identify the burden of disease across these regions and subsequently enable appropriate strategies to be developed to bridge disparities across countries and optimize patient care.

Data availability
The datasets analysed during the current study are available in the GBD repository, http:// ghdx. healt hdata. org/ gbd-resul ts-tool.